This application proposes to evaluate a novel chemical delivery system for estradiol (E2-CDS) which we have demonstrated is "locked-into" the brain and there serves as a depot for the sustained release of the steroid. The delivery system is based upon the chemical attachment of estradiol (E2) to a lipoidal dihydropyridine carrier. This E2-CDS crosses the blood-brain barrier (BBB) and the carrier is rapidly oxidized to the charge, hydrophilic quaternary pyridinium salt (E2-Q+), thus reducing its rate of egress from the brain. The hydrolysis of E2 from the carrier results in the sustained release of the steroid in the brain and the rapid clearance of the non-toxic carrier. In vivo, the E2-CDS causes elevations in brain E2-Q+ and E2 and there both of these metabolites are cleared slowly. As an apparent result, long-lasting effects of E2-CDS are observed, including chronic suppression of LH, suspension of estrous cycles, stimulation of masculine sexual behavior suppression of testosterone secretion and of weight of androgen-responsive tissues and reductions in food intake and body weights. In the present application, we propose to use rats as an animal model (1) to determine the regional, cellular and subcellular distribution in the brain over time of the two major metabolites of the delivery system, E2-Q+ E2 using quantitative autoradiography; (2) to determine the mechanism by which E2-CDS causes chronic suppression in LH secretion; (3) to determine the mechanism by which E2-CDS causes chronic suppression of testosterone secretion; (4) to determine the effects of E2- CDS on the growth of androgen-dependent prostatic adrenocarcinomas; and (5) to compare the efficacy of E2-CDS with LHRH agonists and LHRH agonists plus antiandrogens on the growth of prostatic tumors. The proposed evaluation will provide needed information of the pharmacokinetics, metabolism and pharmacodynamics of this novel E2-chemical delivery system. This knowledge may lead to (1) a useful tool for dissociating central from peripheral effects of estradiol; (2) a potential method for preferentially treating brain estradiol deficiencies in women (i.e., brain-mediated components of the post-menopausal syndrome); (3) the selective reduction in gonadotropin secretion, which would be useful in fertility regulation and (4) a useful new approach for the therapy of certain androgen-dependent diseases, such as prostatic carcinomas.